{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T14:19:04Z","timestamp":1791728344794,"version":"4.3.4"},"reference-count":19,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2020,2,4]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>While disease-modifying therapies exist for heart failure (HF) with reduced left ventricular ejection fraction (LVEF), few options are available for patients in the higher range of LVEF (&gt;40%). Sacubitril\/valsartan has been compared with a renin-angiotensin-aldosterone\u2013system inhibitor alone in 2 similarly designed clinical trials of patients with reduced and preserved LVEF, permitting examination of its effects across the full spectrum of LVEF.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>We combined data from PARADIGM-HF (LVEF eligibility\u226440%; n=8399) and PARAGON-HF (LVEF eligibility\u226545%; n=4796) in a prespecified pooled analysis. We divided randomized patients into LVEF categories: \u226422.5% (n=1269), &gt;22.5% to 32.5% (n=3987), &gt;32.5% to 42.5% (n=3143), &gt; 42.5% to 52.5% (n=1427), &gt; 52.5% to 62.5% (n=2166), and &gt;62.5% (n=1202). We assessed time to first cardiovascular death and HF hospitalization, its components, and total heart failure hospitlizations, all-cause mortality, and noncardiovascular mortality. Incidence rates and treatment effects were examined across categories of LVEF.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              Among 13\u2009195 randomized patients, we observed lower rates of cardiovascular death and HF hospitalization, but similar rates of noncardiovascular death, among patients in the highest versus the lowest groups. Overall sacubitril\/valsartan was superior to renin-angiotensin-aldosterone\u2013system inhibition for first cardiovascular death or heart failure hospitalization (Hazard Ratio [HR] 0.84 [95% CI, 0.78\u20130.90]), cardiovascular death (HR 0.84 [95% CI, 0.76\u20130.92]), heart failure hospitalization (HR 0.84 [95% CI, 0.77\u20130.91]), and all-cause mortality (HR 0.88 [95% CI, 0.81\u20130.96]). The effect of sacubitril\/valsartan was modified by LVEF (treatment-by-continuous LVEF interaction\n              <jats:italic>P<\/jats:italic>\n              =0.02), and benefit appeared to be present for individuals with EF primarily below the normal range, although the treatment benefit for cardiovascular death diminished at a lower ejection fraction. We observed effect modification by LVEF on the efficacy of sacubitril\/valsartan in both men and women with respect to composite total HF hospitalizations and cardiovascular death, although women derived benefit to higher ejection fractions.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>The therapeutic effects of sacubitril\/valsartan, compared with a renin-angiotensin-aldosterone\u2013system inhibitor alone, vary by LVEF with treatment benefits, particularly for heart failure hospitalization, that appear to extend to patients with heart failure and mildly reduced ejection fraction. These therapeutic benefits appeared to extend to a higher LVEF range in women compared with men.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Clinical Trial Registration:<\/jats:title>\n            <jats:p>\n              <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\">https:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n              . Unique identifiers: NCT01920711 (PARAGON-HF), NCT01035255 (PARADIGM-HF).\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.119.044586","type":"journal-article","created":{"date-parts":[[2019,11,17]],"date-time":"2019-11-17T15:45:17Z","timestamp":1574005517000},"page":"352-361","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":508,"title":["Sacubitril\/Valsartan Across the Spectrum of Ejection Fraction in Heart Failure"],"prefix":"10.1161","volume":"141","author":[{"given":"Scott D.","family":"Solomon","sequence":"first","affiliation":[{"name":"Cardiovascular Division, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA (S.D.S., M.V., B.L.C., M.A.P., A.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muthiah","family":"Vaduganathan","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA (S.D.S., M.V., B.L.C., M.A.P., A.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"L. Claggett","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA (S.D.S., M.V., B.L.C., M.A.P., A.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milton","family":"Packer","sequence":"additional","affiliation":[{"name":"Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.)."},{"name":"Imperial College, London, United Kingdom (M.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Zile","sequence":"additional","affiliation":[{"name":"Medical University of South Carolina, Charleston (M.Z.)."},{"name":"Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, SC (M.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Swedberg","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden (K.S.)."},{"name":"National Heart and Lung Institute, Imperial College, London, United Kingdom (K.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Rouleau","sequence":"additional","affiliation":[{"name":"Institut de Cardiologie de Montr\u00e9al, Universit\u00e9 de Montr\u00e9al, Canada (J.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"A. Pfeffer","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA (S.D.S., M.V., B.L.C., M.A.P., A.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akshay","family":"Desai","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA (S.D.S., M.V., B.L.C., M.A.P., A.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"H. Lund","sequence":"additional","affiliation":[{"name":"Department of Medicine, Karolinska Institutet, and Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden (L.H.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Kober","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Heart Centre, Rigshospitalet, Copenhagen University Hospital, Denmark (L.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inder","family":"Anand","sequence":"additional","affiliation":[{"name":"Department of Medicine, VA Medical Center and University of Minnesota, Minneapolis (I.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Sweitzer","sequence":"additional","affiliation":[{"name":"Sarver Heart Center, University of Arizona College of Medicine, Tucson (N.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard","family":"Linssen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Hospital Group Twente, Almelo and Hengelo, The Netherlands (G.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bela","family":"Merkely","sequence":"additional","affiliation":[{"name":"Heart and Vascular Center, Semmelweis University, Budapest, Hungary (B.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Luis Arango","sequence":"additional","affiliation":[{"name":"Guatemalan Heart Institute (J.L.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dragos","family":"Vinereanu","sequence":"additional","affiliation":[{"name":"University of Medicine and Pharmacy Carol Davila, University and Emergency Hospital of Bucharest, Romania (D.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Huan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China (C.-H.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Senni","sequence":"additional","affiliation":[{"name":"Cardiology Division, Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo, Italy (M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Sibulo","sequence":"additional","affiliation":[{"name":"St Luke\u2019s Heart Institute, St. Luke\u2019s Medical Center, Taguig, Philippines (A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergey","family":"Boytsov","sequence":"additional","affiliation":[{"name":"National Research Center for Cardiology of the Ministry of Health of the Russian Federation, Moscow (S.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Shi","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation, East Hanover, NJ (V.S, A.R., M.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adel","family":"Rizkala","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation, East Hanover, NJ (V.S, A.R., M.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Lefkowitz","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation, East Hanover, NJ (V.S, A.R., M.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.V.","family":"McMurray","sequence":"additional","affiliation":[{"name":"British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (J.J.V.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)31808-7"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehw128"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2017.04.025"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.1149"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehv464"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.09.052"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.015884"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.159"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1409077"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1908655"},{"key":"e_1_3_3_12_2","unstructured":"Novartis Position on Clinical Study Transparency \u2013 Clinical Study Registration Results Reporting and Data Sharing 2016. https:\/\/www.novartis.com\/sites\/www.novartis.com\/files\/clinical-trial-data-transparency.pdf. Accessed January 20 2020."},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurjhf\/hft052"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2017.04.013"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4757-3462-1"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000509"},{"key":"e_1_3_3_17_2","article-title":"Cardiac structure and function in heart failure with preserved ejection fraction: the echocardiographic study of the prospective comparison of ARNI with ARB global outcomes in HF with preserved ejection fraction (PARAGON-HF) trial.","author":"Shah AM","unstructured":"Shah, AM, Cikes, M, Prasad, N, Li, G, Getchevsky, S, Claggett, B, Rizkala, A, Lukashevich, I, O\u2019Meara, E, Ryan, JJ, et al. for the PARAGON-HF Investigators. Cardiac structure and function in heart failure with preserved ejection fraction: the echocardiographic study of the prospective comparison of ARNI with ARB global outcomes in HF with preserved ejection fraction (PARAGON-HF) trial. J Am Coll Cardiol. In Press. 10.1016\/j.jacc.2019.09.063","journal-title":"J Am Coll Cardiol"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2013.11.004"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1805689"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmg.2008.04.015"}],"container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCULATIONAHA.119.044586","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T08:21:24Z","timestamp":1715588484000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCULATIONAHA.119.044586"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,4]]},"references-count":19,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2020,2,4]]}},"alternative-id":["10.1161\/CIRCULATIONAHA.119.044586"],"URL":"https:\/\/doi.org\/10.1161\/circulationaha.119.044586","relation":{},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,4]]},"assertion":[{"value":"2019-10-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-11-12","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-11-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}